In A Genetic Portrait Of A Nation, A Map Of The Future

It’s the most complete genetic map of an entire country yet completed – and it could show clues of what medicine could look like in the coming age of big data.

Researchers working at DeCode Genetics, a unit of the drug company Amgen, have sequenced the genomes of 2,636 Icelanders and used genealogical records and more spotty genetic data to calculate the likely genetics of 101,584 more. Because DeCode has anonymized access to patient medical records, the company could then look for relationships between the genetic variants and disease – and they found a new genetic variant that increases the risk of Alzheimer’s, as well as confiming suspected variants that raise the risk of diabetes and one that causes atrial fibrillation, a heart condition. The results are published in three scientific papers in the journal Nature.

“It’s certainly an impressive tour de force,” says George Yancopoulos, the Chief Scientific Officer of Amgen rival Regeneron. “This is certainly establishing a benchmark for all of us and showing the value of this type of analysis, in particular in the Icelandic population.”

Regeneron is creating its own database of sequencing data with Pennsylvania’s Geisinger Health Systems. The United Kingdom has embarked on a 100,000 Genomes Project. And President Obama has proposed linking together lots of ongoing sequencing projects into a database of 1 million volunteers. The DeCode experiment, started 18 years ago during the dot-com boom, is our first look at the kind of data that these gargantuan efforts could produce.

Some important basic science questions were answered. For instance, a lot of effort is put into figuring out when the most recent common male ancestor of all people has lived, an area of research that could be important for understanding of diseases linked to the (male) Y chromosome. But Amgen bought DeCode, and its access to Iceland’s population for $415 million two years ago. It didn’t spend that kind of coin to find out about the mutation rate on the Y chromosome.

The hope has always been that these kinds of genetic data would lead to new drugs. And DeCode provides a series of huge leads. Scientists frequently try to figure out what genes do by ‘knocking them out’ (that is, breaking them) in mice. Doing the same experiment in humans would be, of course, highly unethical.

Except that some people are born with naturally dysfunctional copies of some genes. And these can be clues to drugs. There’s even a great example: having a dysfunctional version of a gene called PCSK9 results in lower cholesterol levels and rates of heart disease. There are even people with two broken copies of the gene, including an aerobics instructor in Dallas who has levels of LDL, or bad cholesterol, of 14 milligrams per deciliter, compared to normal levels of more than 100 mg/dL.

Both Amgen and Regeneron have drugs (evolocumab and alirocumab) that block PCSK9 that will soon hit the market, in what is expected to be one of the most heated drug launches in years. Drug company executives hope that more genetic data would mean finding more genes like PCSK9 that could be useful drug targets.

DeCode delivered in spades. One of the Nature papers published today found a huge collection of human knockouts – people who have a dysfunctional version of one gene. (Each of us usually have two copies of every gene – one from each parent.) They found 8,000 people who had both copies of a gene either partly or entirely knocked out. Because the deal with Iceland that created DeCode gives it access to medical records, it will now start the process of studying and following those people looking for leads for creating new drugs.

DeCode’s set-up will make this faster, but some experts believe that larger, more diverse databases will allow them to find even more human knockouts. “I can speak in all hope that some fraction of those genes will also lead to more drug targets,” says Daniel MacArthur, the group leader of the Analytic and Translational Genetics Unit (ATGU) at Massachusetts General Hospital. “It’s a taste of what we can do with even bigger and more diverse populations.”

Meanwhile, the great DeCode experiment, started by the company’s founder Kari Stefansson, then a Harvard neurologist and geneticist, in the late 1990s, also yields other kids of ethical questions. Since doctors started doing genetic studies, the consensus has been that if you find out about a gene in a research study, you should not return that result to participants. But Stefansson asks if that’s really the right approach.

What about women who have the BRCA gene, which confers a higher risk of breast cancer and ovarian cancer? (This is the gene that led Angelina Jolie to have a mastectomy and oophorectomy.) In the Icelandic population, those women, Stefansson says, have an 86% chance of having their lives shortened by cancer, but preventative surgery can change that. Do they need to be asked whether they want to know about their BRCA mutation, or should they simply be told?

“I am an old-fashioned physician, and if I know of people who are at an 86% risk of cancer I just want to go with them and prevent this from happening,” Stefansson says. “But there are those who want to approach them indirectly. That is the debate for society.”